EP0321812A1 - 4,8-Dihydro-8-arylisoxazolo[4,3-e][1,4]-oxazépin-5(6H)-ones, un procédé pour leur préparation et leur utilisation comme médicaments - Google Patents

4,8-Dihydro-8-arylisoxazolo[4,3-e][1,4]-oxazépin-5(6H)-ones, un procédé pour leur préparation et leur utilisation comme médicaments Download PDF

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Publication number
EP0321812A1
EP0321812A1 EP88120673A EP88120673A EP0321812A1 EP 0321812 A1 EP0321812 A1 EP 0321812A1 EP 88120673 A EP88120673 A EP 88120673A EP 88120673 A EP88120673 A EP 88120673A EP 0321812 A1 EP0321812 A1 EP 0321812A1
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EP
European Patent Office
Prior art keywords
oxazepin
dihydro
loweralkyl
compound
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP88120673A
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German (de)
English (en)
Inventor
John Joseph Tegeler
Kirk David Shoger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharmaceuticals Inc
Original Assignee
Hoechst Roussel Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoechst Roussel Pharmaceuticals Inc filed Critical Hoechst Roussel Pharmaceuticals Inc
Publication of EP0321812A1 publication Critical patent/EP0321812A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to compounds of the formula I wherein R1 is hydrogen, loweralkyl, arylloweralkyl, aryloxyloweralkyl, cycloalkylloweralkyl, aminoloweralkyl, loweralkylaminoloweralkyl, diloweralkylaminoloweralkyl, and loweralkoxycarbonylloweralkyl; R2 is hydrogen or loweralkyl; Y is independently loweralkyl, loweralkoxy, halogen, trifluoromethyl or nitro; and n is an integer having a value from 0 to 2, inclusive; the geometrical isomers; optical antipodes or pharmaceutically acceptable acid addition salts thereof.
  • the 4,8-dihydro-8-arylisoxazolo[4,3-e][1,4]oxazepin-5(6H)-ones of this invention are useful as antihypertensive agents.
  • “Loweralkyl” a linear or branched, acyclic hydrocarbon radical containing no unsaturation and having the formula -C x H 2x+1 wherein x is an integer having a value of 1 to 7, inclusive, such a methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 3-hexyl, 4-heptyl, and the like.
  • “Loweralkoxy” an acylic organic radical of the formula -OC x H 2x+1 wherein x is an integer having a value of 1 to 7, inclusive, such a methoxy, ethoxy, 1- and 2-propoxy, 1,2-dimethylethoxy, 1-butoxy, 1- and 2-pentoxy, 3-hexoxy, 4-heptoxy, and the like.
  • “Cycloalkyl” - a cyclic hydrocarbon radical of the formula -C x H 2x-1 wherein x is an integer having a value of 3 to 7, inclusive, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Aryl - a phenyl group optionally substituted by up to 3 substituents each of which is independently loweralkyl, loweralkoxy, halogen, trifluoromethyl, nitro or cyano.
  • Aryloxy - a monovalent substituent which consists of an aryl group liked through an ether oxygen and having its free valence bond from the ether oxygen.
  • Halogen - a member of the group consisting of fluorine, chlorine, bromine, and iodine radicals.
  • Arylloweralkyl - a loweralkyl group having an aryl substituent thereon.
  • Aryloxyloweralkyl - a loweralkyl group having an aryloxy substituent thereon.
  • Cycloalkylloweralkyl - a loweralkyl group having a cycloalkyl substituent thereon.
  • Amino - a group of the formula -NH2.
  • “Loweralkylamino”- a group of the formula wherein alk is loweralkyl.
  • Aminoloweralkyl - a loweralkyl group having an amino substituent thereon.
  • Loweralkylaminoloweralkyl a loweralkyl group having a loweralkylamino substituent thereon.
  • Diloweralkylaminoloweralkyl a loweralkyl group having a diloweralkylamino substituent thereon.
  • a (4-aminoisoxazol-3-yl)phenylmethanone 1 is chloroacetylated to an N-(3-benzoylisoxazol-4-yl)chloroacetamide 2 which is converted to an N-[3-(1-phenyl-1-hydroxyalkyl)-5-methylisoxazol-4-yl]chloroacetamide 3 and then cyclized.
  • the (4-aminoisoxazol-3-yl)phenylmethanone 1 starting material is known in the art. See, for example, U.S. Patent No. 4,544,793 describing the preparation of same.
  • Chloroacetylation is accomplished by reacting the (4-aminoisoxazol-3-yl)phenylmethanone 1 with chloroacetyl chloride at a temperature of from about -20°C to about 40°C, preferably from about 0°C to about 10°C in a suitable solvent.
  • Suitable solvents include halogenated hydrocarbons, ethereal solvents and the like such as, for example, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, dimethoxyethane, and the like. Dichloromethane is preferred.
  • the reaction is generally conducted in the presence of a suitable acid scavenger.
  • Suitable acid scavengers include alkali metal carbonates, alkali metal bicarbonates, and tertiary amines (e.g. potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, and the like).
  • Conversion of the chloroacetamide 2 to the corresponding 1-phenyl-1-hydroxyalkyl derivative 3 is typically accomplished by reaction with an appropriate organolithium or Grignard reagent (i.e. a compound of the formula R2Li or R2MgX wherein R2 is loweralkyl and X is halogen, preferably chlorine or bromine.
  • organolithium or Grignard reagent i.e. a compound of the formula R2Li or R2MgX wherein R2 is loweralkyl and X is halogen, preferably chlorine or bromine.
  • the reaction is ordinarily conducted in a non-reactive organic solvent at a temperature of from about -70°C to the reflux temperature of the solvent, preferably from about -35°C to about 0°C.
  • Suitable solvents for the reaction include ethereal solvents such as diethyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, and the
  • Cyclization of the chloroacetamide 3 to the parent system 4 is achieved by reaction with a suitable base (e.g. alkali metal hydrides; sodium hydride being preferred) at a temperature of from about 20°C to the reflux temperature of the solvent medium, reflux temperatures being preferred.
  • a suitable base e.g. alkali metal hydrides; sodium hydride being preferred
  • Suitable solvents for the cyclization include ethereal solvents as previously described, tetrahydrofuran being preferred.
  • Substitution of the parent system at the nitrogen atom of the oxazepin ring is achieved by treating the parent system 4 with a suitable base (e.g. alkali metal hydrides, sodium hydride being preferred) and a compound of the formula R1X wherein R1 is loweralkyl, aralkyl, aryloxyloweralkyl, cycloalkylloweralkyl, aminoloweralkyl, loweralkylaminoloweralkyl, diloweralkylaminoloweralkyl, or loweralkoxycarbonylloweralkyl and X is halogen, preferably iodine, except when R1 is aminoloweralkyl, loweralkylaminoloweralkyl or diloweralkylaminoloweralkyl, then preferably chlorine.
  • a suitable base e.g. alkali metal hydrides, sodium hydride being preferred
  • R1X is halogen, preferably iodine, except when R1
  • the alkylation is generally conducted in a nonreactive organic solvent for example polar aprotic solvents such as for example dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, and the like (dimethylformamide being preferred), at a temperature of from about 0°C to about 120°C, preferably from about 20°C to about 100°C.
  • polar aprotic solvents such as for example dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, and the like (dimethylformamide being preferred
  • Antihypertensive activity is measured in the spontaneous hypertensive rat by the indirect tail cuff method described by A. Schwartz, Ed., Methods in Pharmacology , Vol. I, page 135, Appleton Century Crafts, New York (1971). In this procedure, a group of five animals is treated orally with the drug for three days in relation to a control group of the same number. The drop in blood pressure is measured on the third day following administration. The antihypertensive activity is expressed as mm Hg decrease in systolic blood pressure.
  • the compounds of this invention are effective in the treatment of hypertension when administered orally, intraperitoneally or intraveneously to a subject requiring such treatment at a dose of from about 0.1 to about 60 mg/kg of body weight per day.
  • the aforesaid compounds may be incorporated with excipients, diluents and/or carriers and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • These preparations should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% and 70% of the weight of the unit.
  • the amount of active compound is such that a suitable dosage will be obtained.
  • Preferred compositions and preparations according to the present invention are prepared so that an oral dosage form contains between 1.0 and 300 milligrams of the active compound.
  • the tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, corn starch and the like; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, corn starch and the like
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin or a flavoring agent such as pepper
  • dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but may be varied between 0.5 and about 50% of the weight thereof. The amount of active compounds in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 and 100 milligrams of active compound.
  • the solutions or suspensions for parenteral administration may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as ethylenediaminetetraace

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
EP88120673A 1987-12-21 1988-12-10 4,8-Dihydro-8-arylisoxazolo[4,3-e][1,4]-oxazépin-5(6H)-ones, un procédé pour leur préparation et leur utilisation comme médicaments Withdrawn EP0321812A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/135,763 US4800200A (en) 1987-12-21 1987-12-21 4,8-dihydro-8-arylisoxazolo[4,3-e][1,4]-oxazepin-5(6H)-ones
US135763 1987-12-21

Publications (1)

Publication Number Publication Date
EP0321812A1 true EP0321812A1 (fr) 1989-06-28

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EP88120673A Withdrawn EP0321812A1 (fr) 1987-12-21 1988-12-10 4,8-Dihydro-8-arylisoxazolo[4,3-e][1,4]-oxazépin-5(6H)-ones, un procédé pour leur préparation et leur utilisation comme médicaments

Country Status (5)

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US (1) US4800200A (fr)
EP (1) EP0321812A1 (fr)
JP (1) JPH01258680A (fr)
DK (1) DK710688A (fr)
PT (1) PT89281A (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103380155B (zh) 2011-02-14 2016-02-03 住友精化株式会社 亲水性增稠剂以及其制造方法
WO2018144975A1 (fr) 2017-02-06 2018-08-09 Huntsman Petrochemical Llc Agent de durcissement pour des résines époxydes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1944468A1 (de) * 1968-09-03 1970-03-12 Upjohn Co Perhydro-5-phenyl-cycloalkapolyen-4,1-oxazepine und Verfahren zu deren Herstellung
EP0013749A1 (fr) * 1979-01-13 1980-08-06 BASF Aktiengesellschaft Hexahydro-1,4-oxazépines, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0109622A1 (fr) * 1982-11-20 1984-05-30 BASF Aktiengesellschaft Phényl-7-phénoxyméthyl-7-hexahydro-oxazépines-1,4, leur préparation et leur application
US4514410A (en) * 1984-05-31 1985-04-30 Hoechst-Roussel Pharmaceuticals Inc. Substituted 8-phenylisoxazolo[4,3-e][1,4]diazepin-5-ones

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3891630A (en) * 1974-03-04 1975-06-24 Abbott Lab Substituted pyrazolo{8 3,4-e{9 {8 1,4{9 thiazepines and isoxazolo{8 5,4-e{9 {8 1,4{9 thiazepines
EP0142361B1 (fr) * 1983-11-17 1988-05-11 The Upjohn Company 5-Phényl-4,1-benzoxazépine-2(3H)-ones N-substituées à activité thérapeutique utile
US4590187A (en) * 1983-11-17 1986-05-20 The Upjohn Company Phospholipase A2 inhibition using 4,1-benzoxazepine-2-(3H)-ones

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1944468A1 (de) * 1968-09-03 1970-03-12 Upjohn Co Perhydro-5-phenyl-cycloalkapolyen-4,1-oxazepine und Verfahren zu deren Herstellung
EP0013749A1 (fr) * 1979-01-13 1980-08-06 BASF Aktiengesellschaft Hexahydro-1,4-oxazépines, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0109622A1 (fr) * 1982-11-20 1984-05-30 BASF Aktiengesellschaft Phényl-7-phénoxyméthyl-7-hexahydro-oxazépines-1,4, leur préparation et leur application
US4514410A (en) * 1984-05-31 1985-04-30 Hoechst-Roussel Pharmaceuticals Inc. Substituted 8-phenylisoxazolo[4,3-e][1,4]diazepin-5-ones

Also Published As

Publication number Publication date
PT89281A (pt) 1989-12-29
JPH01258680A (ja) 1989-10-16
US4800200A (en) 1989-01-24
DK710688D0 (da) 1988-12-20
DK710688A (da) 1989-06-22

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Free format text: 4,8-DIHYDRO-8-ARYLISOXAZOLO??4,3-E ??1,4 -OXAZEPIN-5(6H)-ONES, A PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS